Azzindani/Open_Reaction_Data huggingface dataset:
Reaction SMILES: Cl[CH2:2][CH2:3][CH2:4][C:5]([C:7]1[CH:19]=[CH:18][C:17]2[C:16]3[C:11](=[CH:12][C:13]([C:20](=[O:25])[CH2:21][CH2:22][CH2:23]Cl)=[CH:14][CH:15]=3)[CH2:10][C:9]=2[CH:8]=1)=[O:6].[NH:26]1[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1.[I-].[K+].O>CC(=O)CC>[N:26]1([CH2:2][CH2:3][CH2:4][C:5]([C:7]2[CH:19]=[CH:18][C:17]3[C:16]4[C:11](=[CH:12][C:13]([C:20](=[O:25])[CH2:21][CH2:22][CH2:23][N:26]5[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]5)=[CH:14][CH:15]=4)[CH2:10][C:9]=3[CH:8]=2)=[O:6])[CH2:31][CH2:30][CH2:29][CH2:28][CH2:27]1
Reactant: C1CCNCC1
Reactant: O=C(CCCCl)c1ccc2c(c1)Cc1cc(C(=O)CCCCl)ccc1-2
Agent: [I-]
Agent: [K+]
Solvent: O
Solvent: CCC(C)=O
Product: O=C(CCCN1CCCCC1)c1ccc2c(c1)Cc1cc(C(=O)CCCN3CCCCC3)ccc1-2

Procedure:
A mixture of 18.8 g (0.05 mole) of 2,7-bis(4-chlorobutyryl)fluorene, prepared in Example 10, 34.0 g (0.4 mole) of piperidine, 16.6 g (0.1 mole) of potassium iodide in 200 ml of butanone is stirred and refluxed for three days. The reaction mixture is poured into 1000 ml of water, and the solid which is precipitated is filtered and recrystallized twice from chlorform-acetone to give 2,7-bis(4-piperidinobutyryl)fluorene, M.P. 157°-159°C.
Reaction SMILES: [CH3:1][NH:2][C:3](=O)[O:4]C1C=CC([N+]([O-])=O)=CC=1.C(N(CC)C(C)C)(C)C.[Cl:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([NH:31][NH2:32])=[O:30])=[CH:27][CH:26]=1>ClCCl>[Cl:24][C:25]1[CH:34]=[CH:33][C:28]([C:29]([NH:31][NH:32][C:3]([NH:2][CH3:1])=[O:4])=[O:30])=[CH:27][CH:26]=1
Reactant: CNC(=O)Oc1ccc([N+](=O)[O-])cc1
Reactant: NNC(=O)c1ccc(Cl)cc1
Solvent: ClCCl
Solvent: CCN(C(C)C)C(C)C
Product: CNC(=O)NNC(=O)c1ccc(Cl)cc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
575 mg (2.93 mmol) of 4-nitrophenyl methylcarbamate and 417 mg (3.22 mmol) of N,N-diisopropylethylamine are successively added to 500 mg (2.93 mmol) of 4-chlorobenzoic acid hydrazide in 15 ml dichloromethane and the mixture stirred overnight at room temperature. It is concentrated, the residue is purified by preparative HPLC [Method 9] and 410 mg (61% of theory) of the target compound are thus obtained.
Reaction SMILES: [Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@@H:18]3[CH2:23][O:22][C:21]([CH3:25])([CH3:24])[CH2:20][NH:19]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1.C(N(CC)CC)C.C([BH3-])#N.[Na+].[C:37]([OH:41])(=[O:40])[CH:38]=O>CO.O>[Cl:1][C:2]1[CH:3]=[C:4]2[C:12](=[C:13]([NH:15][C:16]([C@H:18]3[N:19]([CH2:38][C:37]([OH:41])=[O:40])[CH2:20][C:21]([CH3:25])([CH3:24])[O:22][CH2:23]3)=[O:17])[CH:14]=1)[NH:11][C:10]1[CH:9]=[N:8][CH:7]=[CH:6][C:5]2=1
Reactant: CC1(C)CN[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Reactant: O=CC(=O)O
Agent: [BH3-]C#N
Agent: [Na+]
Solvent: CO
Solvent: CCN(CC)CC
Solvent: O
Product: CC1(C)CN(CC(=O)O)[C@H](C(=O)Nc2cc(Cl)cc3c2[nH]c2cnccc23)CO1
Temperature: 25 °C
Reaction time: 1.5 h
Yield: 72 %

Procedure:
To a suspension of (S)-6,6-Dimethyl-morpholine-3-carboxylic acid (6-chloro-9H-beta-carbolin-8-yl)-amide (2.6 g, 6.0 mmoles) in 60 ml of methanol was added 1.7 ml of triethylamine (2.0 eq.), sodium cyanoborohydride (575 mg, 9.1 mmoles) and glyoxylic acid (780 mg, 8.5 mmoles). The reaction mixture was stirred at ambient temperature for 1.5 hrs. Water was added (5 ml) and the mixture was concentrated to a thick yellow slurry. More water was then added (30 ml) and the resulting slurry was stirred at ambient temperature for 10 min. and was filtered. The collected yellow solid was washed with water and dried under high vacuum to give 1.80 g (71%) of the desired product. 1H-NMR (300 MHz, DMSO-d6): δ 1.17 (s,3H), 1.30 (s,3H), 2.81 (d,1H), 3.34 (d,1H), 3.46 (d,1H), 3.56 (dd,1H), 3.84-3.90 (m,2H), 7.92 (s,1H), 8.15 (d,1H), 8.21 (s,1H), 8.36 (d,1H), 9.01 (s,1H), 10.28 (s,1H), 11.40 (s,1H). Retention Time (LC, method: ammonium acetate standard): 1.26 min. MS (M+H+): 417.1.
Reaction SMILES: [CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:4]=1[CH2:5][C@H:6]1[NH:11][CH2:10][CH2:9][O:8][C@@H:7]1[CH2:12]2.[CH2:17]=O.[H][H]>[Pd].CO>[CH3:1][O:2][C:3]1[CH:16]=[CH:15][CH:14]=[C:13]2[C:4]=1[CH2:5][C@H:6]1[N:11]([CH3:17])[CH2:10][CH2:9][O:8][C@@H:7]1[CH2:12]2
Reactant: C=O
Reactant: [H][H]
Reactant: COc1cccc2c1C[C@H]1NCCO[C@@H]1C2
Agent: [Pd]
Solvent: CO
Product: COc1cccc2c1C[C@@H]1[C@@H](C2)OCCN1C
Reaction time: 6 h

Procedure:
2 g of palladium on charcoal (10%) are suspended in 100 ml of methanol. To this are added 4.82 g (0.022M) of trans-3,4,4a,5,10,10a-hexahydro-6-methoxy-2H-naphth[2,3-b]-1,4-oxazine and 23.65 ml of formalin (37%), both dissolved in a total of 200 ml of methanol. The mixture is subsequently hydrogenated at 20°, at 1.2 bar hydrogen pressure. After 6 hours, the reaction mixture is filtered through a Hyflo suction filter, washed with 100 ml of methylene chloride, and the filtrate is concentrated by evaporation. The residue is taken up again in 100 ml of methylene chloride, and washed once each time with 20 ml of saturated potassium carbonate solution and water. The methylene chloride phase is dried and concentrated by evaporation. Trans-3,4,4a,5,10,10a-hexahydro-6-methoxy-4-methyl-2H-naphth[2,3-b]-1,4-oxazine is obtained (m.p. 268°-270°, recrystallisation from methylene chloride, methanol, acetone).
Reaction SMILES: C([Mg:3][Br:4])C.[C:5]1(=[O:12])[NH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1>C(OCC)C>[C:5]1(=[O:12])[NH:11][CH2:10][CH2:9][CH2:8][CH2:7][CH2:6]1.[Br:4][Mg:3]
Reactant: CC[Mg]Br
Agent: O=C1CCCCCN1
Solvent: CCOCC
Product: [Mg]Br
Reaction time: 0.08 h

Procedure:
In a second flask a 0.23 molar bromomagnesium caprolactam solution was prepared by adding 15 ml of a 3 molar ethyl magnesium bromide in diethyl ether solution to 200 gms dry caprolactam. Then 2.12 ml (2.0 gm) of a polyoxypropylene diamine (approximate m.w. 230) was added. The equivalents of primary and secondary amines of the polyfunctional amine were 30 percent of the acyl lactam group equivalent of the acyl lactam functionalized material. The material of the two flasks were injected into a mold as described above for Example 1. After 5 minutes, the casting was removed from the mold to give a nylon block copolymer containing 40% polyether.
Reaction SMILES: C1(C)C=CC(S(O[CH2:11][C@@H:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)(=O)=O)=CC=1.[F:27][C:28]([F:38])([F:37])[C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH2:34])=[CH:31][CH:30]=1.O>CS(C)=O>[F:27][C:28]([F:37])([F:38])[C:29]1[CH:36]=[CH:35][C:32]([CH2:33][NH:34][CH2:11][CH:12]2[O:25][C:16]3=[C:17]4[C:21](=[CH:22][CH:23]=[C:15]3[O:14][CH2:13]2)[NH:20][C:19](=[O:24])[CH2:18]4)=[CH:31][CH:30]=1
Reactant: NCc1ccc(C(F)(F)F)cc1
Reactant: Cc1ccc(S(=O)(=O)OC[C@H]2COc3ccc4c(c3O2)CC(=O)N4)cc1
Solvent: CS(C)=O
Solvent: O
Product: O=C1Cc2c(ccc3c2OC(CNCc2ccc(C(F)(F)F)cc2)CO3)N1
Temperature: 85 °C
Yield: 53.8 %

Procedure:
(R)-2-(Toluene-4-sulfonyloxymethyl)-2,3,8,9-tetrahydro-7H-1,4-dioxino[2,3-e]indol-8-one (1.03 g, 2.75 mmole) and 4-trifluoromethylbenzylamine (1.60 ml, 11.2 mmole) were combined in 15 ml of dry DMSO and heated to 85° C. for 3.5 hours under a nitrogen atmosphere. After cooling to room temperature, 150 ml of water was added and the mixture was extracted twice with 250 ml portions of 35% ethyl acetate in hexane. The combined organic phases were washed with brine, dried over MgSO4, filtered and concentrated in vacuum to yield an oil, which was column chromatographed on silica gel using 5% methanol/CH2Cl2 as eluant. The free base of the title compound (0.56 g, 54%) thus obtained was crystallized from ethanol with the addition of one equivalent of fumaric acid to give 0.06 g of the (S) enantiomer of the title compound as an off-white solid fumarate, m.p. 211°-212° C.
Reaction SMILES: [Cl:1][C:2]1[CH:15]=[CH:14][C:5]([CH2:6][N:7]2[CH2:12][CH2:11][CH:10]([OH:13])[CH2:9][CH2:8]2)=[CH:4][CH:3]=1.CN(C1C=CC=CN=1)C.[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30](O)=[O:31])=[CH:28][CH:27]=1.Cl.C(N=C=NCCCN(C)C)C>CN(C)C=O>[F:25][C:26]1[CH:34]=[CH:33][C:29]([C:30]([O:13][CH:10]2[CH2:9][CH2:8][N:7]([CH2:6][C:5]3[CH:4]=[CH:3][C:2]([Cl:1])=[CH:15][CH:14]=3)[CH2:12][CH2:11]2)=[O:31])=[CH:28][CH:27]=1
Reactant: OC1CCN(Cc2ccc(Cl)cc2)CC1
Reactant: O=C(O)c1ccc(F)cc1
Agent: CCN=C=NCCCN(C)C
Agent: CN(C)c1ccccn1
Agent: Cl
Solvent: CN(C)C=O
Product: O=C(OC1CCN(Cc2ccc(Cl)cc2)CC1)c1ccc(F)cc1
Temperature: 25 °C
Reaction time: 72 h
Yield: 83.4 %

Procedure:
0.226 g (0.001 mol) of 1-(4-chloro-benzyl)-piperidin-4-ol was dissolved in 5 ml of dimethylformamide and treated with 0.061 g (0.0005 mol) of dimethylaminopyridine and 0.14 g (0.001 mol) of 4-fluoro-benzoic acid. The mixture was cooled to 0° and 0.211 g (0.0011 mol) of N-ethyl-N'-(3-dimethylamino-propyl)-carbodiimide hydrochloride was added. The mixture was warmed to room temperature and stirred for 72 hrs. The solvent was distilled off and the residue was taken up in ethyl acetate and treated with silica gel. After removal of the solvent the residue was chromatographed on silica gel with ethyl acetate/hexane (1:2) as the eluent. 0.29 g (83%) of 1-(4-chloro-benzyl)-piperidin-4-yl 4-fluoro-benzoate was obtained as a colorless oil.
Reaction SMILES: [CH3:1][N:2]([CH3:14])[C:3]([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][OH:13])[N:7]=[CH:6]1)=[O:4].C(N(CC)CC)C.Cl[Si:23]([CH3:26])([CH3:25])[CH3:24]>C(#N)C.CCOCC>[CH3:14][N:2]([CH3:1])[C:3]([N:5]1[CH:9]=[C:8]([CH2:10][CH2:11][CH2:12][O:13][Si:23]([CH3:26])([CH3:25])[CH3:24])[N:7]=[CH:6]1)=[O:4]
Reactant: CN(C)C(=O)n1cnc(CCCO)c1
Reactant: C[Si](C)(C)Cl
Solvent: CCOCC
Solvent: CC#N
Solvent: CCN(CC)CC
Product: CN(C)C(=O)n1cnc(CCCO[Si](C)(C)C)c1
Reaction time: 15 h

Procedure:
1-Dimethylcarbamoyl-4-(3-hydroxypropyl)-imidazole (19.8 g, 0.10 mole) and triethylamine (15 g, 0.15 mole) are dissolved in acetonitrile (100 mL) and the solution is stirred and cooled in an ice bath during the dropwise addition of chlorotrimethylsilane (11.9 g, 0.11 mole). The reaction is stirred at ice-bath temperature for 1 hour and is subsequently allowed to stand at ambient temperature for 15 hours. The mixture is diluted with ether (500 mL), filtered, and the solvent is evaporated to give 1-dimethylcarbamoyl-4-(3-trimethylsilyloxypropyl)imidazole as an oil; NMR (imidazole protons): 2.2 (s) and 3.05 (s) ppm.
Reaction SMILES: [F:1][C:2]([F:34])([F:33])[CH2:3][NH:4][C:5]([NH:7][C:8]1[CH:9]=[C:10]([C:14]2[N:18]3[N:19]=[CH:20][C:21]([C:23]4[CH:24]=[N:25][N:26]([CH:28]([CH3:32])[C:29]([OH:31])=O)[CH:27]=4)=[CH:22][C:17]3=[N:16][CH:15]=2)[CH:11]=[CH:12][CH:13]=1)=[O:6].Cl.[NH:36]1[CH2:39][CH:38]([OH:40])[CH2:37]1>>[OH:40][CH:38]1[CH2:39][N:36]([C:29](=[O:31])[CH:28]([N:26]2[CH:27]=[C:23]([C:21]3[CH:20]=[N:19][N:18]4[C:14]([C:10]5[CH:9]=[C:8]([NH:7][C:5]([NH:4][CH2:3][C:2]([F:1])([F:33])[F:34])=[O:6])[CH:13]=[CH:12][CH:11]=5)=[CH:15][N:16]=[C:17]4[CH:22]=3)[CH:24]=[N:25]2)[CH3:32])[CH2:37]1
Reactant: OC1CNC1
Reactant: CC(C(=O)O)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1
Agent: Cl
Product: CC(C(=O)N1CC(O)C1)n1cc(-c2cnn3c(-c4cccc(NC(=O)NCC(F)(F)F)c4)cnc3c2)cn1

Procedure:
This compound was prepared by using procedures analogous to those described for the synthesis of Example 54, Step 3 starting from 2-(4-{3-[3-({[(2,2,2-trifluoroethyl)amino]carbonyl}amino)phenyl]imidazo[1,2-b]pyridazin-7-yl}-1H-pyrazol-1-yl)propanoic acid and azetidin-3-ol hydrochloride (Oakwood and Cat. No. 013898). LCMS (M+H)+: m/z=529.2.
Reaction SMILES: Cl[C:2]1[C:3]([C:20]#[N:21])=[C:4]([C:14]2[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=2)[C:5]2[C:10](=[O:11])[NH:9][C:8](=[O:12])[NH:7][C:6]=2[N:13]=1.[S-2:22].[Na+].[Na+].Cl[CH2:26][C:27]1[N:28]=[C:29]([C:32]2[CH:37]=[CH:36][C:35]([Cl:38])=[CH:34][CH:33]=2)[S:30][CH:31]=1.C(=O)(O)[O-].[Na+]>CN(C=O)C.O>[Cl:38][C:35]1[CH:36]=[CH:37][C:32]([C:29]2[S:30][CH:31]=[C:27]([CH2:26][S:22][C:2]3[C:3]([C:20]#[N:21])=[C:4]([C:14]4[CH:19]=[CH:18][CH:17]=[CH:16][CH:15]=4)[C:5]4[C:10](=[O:11])[NH:9][C:8](=[O:12])[NH:7][C:6]=4[N:13]=3)[N:28]=2)=[CH:33][CH:34]=1
Reactant: [S-2]
Reactant: N#Cc1c(Cl)nc2[nH]c(=O)[nH]c(=O)c2c1-c1ccccc1
Reactant: ClCc1csc(-c2ccc(Cl)cc2)n1
Agent: O=C([O-])O
Agent: [Na+]
Solvent: O
Solvent: CN(C)C=O
Product: N#Cc1c(SCc2csc(-c3ccc(Cl)cc3)n2)nc2[nH]c(=O)[nH]c(=O)c2c1-c1ccccc1
Temperature: 25 °C
Reaction time: 8 h

Procedure:
100 mg (0.275 mmol) of the compound from Example 9A were dissolved in 0.55 ml of DMF, 25 mg (0.329 mmol) of sodium sulfide were added and the mixture was stirred at RT overnight. The reaction solution was then diluted with 1 ml of DMF, 74 mg (0.302 mmol) of 4-(chloromethyl)-2-(4-chlorophenyl)-1,3-thiazole and 69 mg (0.825 mmol) of sodium bicarbonate were added and the mixture was stirred at RT for 45 min. Water was added to the reaction mixture. The precipitate formed was triturated with THF/Methanol (5 ml/2 ml) and then filtered off. This gave 21 mg (15% of theory) of the product as a solid. For further purification, the filtrate was purified by preparative HPLC (Chromasil, water/acetonitrile+0.1% TFA). This gave another 70 mg (50% of theory) of the product.
Reaction SMILES: Br[C:2]1[CH:3]=[C:4]([CH:29]=[CH:30][CH:31]=1)[C:5]([NH:7][CH:8]([C:10]1[N:15]=[N:14][C:13]([NH:16][C:17]2[CH:22]=[C:21]([O:23][CH3:24])[C:20]([O:25][CH3:26])=[C:19]([O:27][CH3:28])[CH:18]=2)=[N:12][CH:11]=1)[CH3:9])=[O:6].NC(C1N=NC(NC2C=C(OC)C(OC)=C(OC)C=2)=NC=1)C.[CH3:54][O:55][C:56](C1C=CC(C(O)=O)=CC=1)=[O:57].C(N(C(C)C)CC)(C)C.F[P-](F)(F)(F)(F)F.N1(OC(N(C)C)=[N+](C)C)C2N=CC=CC=2N=N1>CN(C)C=O>[CH3:28][O:27][C:19]1[CH:18]=[C:17]([NH:16][C:13]2[N:14]=[N:15][C:10]([CH:8]([NH:7][C:5]([C:4]3[CH:29]=[CH:30][C:31]([C:56]([O:55][CH3:54])=[O:57])=[CH:2][CH:3]=3)=[O:6])[CH3:9])=[CH:11][N:12]=2)[CH:22]=[C:21]([O:23][CH3:24])[C:20]=1[O:25][CH3:26]
Reactant: COC(=O)c1ccc(C(=O)O)cc1
Reactant: COc1cc(Nc2ncc(C(C)NC(=O)c3cccc(Br)c3)nn2)cc(OC)c1OC
Agent: CN(C)C(On1nnc2cccnc21)=[N+](C)C
Agent: COc1cc(Nc2ncc(C(C)N)nn2)cc(OC)c1OC
Agent: F[P-](F)(F)(F)(F)F
Solvent: CCN(C(C)C)C(C)C
Solvent: CN(C)C=O
Product: COC(=O)c1ccc(C(=O)NC(C)c2cnc(Nc3cc(OC)c(OC)c(OC)c3)nn2)cc1
Yield: 100 %

Procedure:
In a similar manner as described for Intermediate 18, 6-(1-aminoethyl)-N-(3,4,5-trimethoxyphenyl)-1,2,4-triazin-3-amine (Intermediate 9) (87 mg, 0.28 mmol), 4-(methoxycarbonyl)benzoic acid (67 mg, 0.37 mmol), diisopropylethylamine (0.13 mL, 0.75 mmol) and O-(7-azabenzotriazol-1-yl)-N,N,N′,N′-tetramethyluronium hexafluorophosphate (140 mg, 0.37 mmol) in dimethylformamide (2 mL) gave methyl 4-{[(1-{3-[(3,4,5-trimethoxyphenyl)amino]-1,2,4-triazin-6-yl}ethyl)amino]carbonyl}benzoate (131 mg, 100%) as a yellow oil. MS m/z 467 (M+1).
Reaction SMILES: [C:1]([N:8]([CH3:42])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:30][C:31]2[CH:32]=[C:33](B(O)O)[CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:16]([C:18]2[S:22][C:21]3[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:20]=3[C:19]=2[Cl:29])=[O:17])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2].Br[C:44]1[CH:49]=[CH:48][N:47]=[C:46]([N:50]([CH3:58])[C:51](=[O:57])[O:52][C:53]([CH3:56])([CH3:55])[CH3:54])[CH:45]=1>>[C:1]([N:8]([CH3:42])[CH:9]1[CH2:14][CH2:13][CH:12]([N:15]([CH2:30][C:31]2[CH:32]=[C:33]([C:44]3[CH:49]=[CH:48][N:47]=[C:46]([N:50]([CH3:58])[C:51](=[O:57])[O:52][C:53]([CH3:54])([CH3:55])[CH3:56])[CH:45]=3)[CH:34]=[CH:35][C:36]=2[O:37][CH3:38])[C:16]([C:18]2[S:22][C:21]3[C:23]([F:28])=[CH:24][CH:25]=[C:26]([F:27])[C:20]=3[C:19]=2[Cl:29])=[O:17])[CH2:11][CH2:10]1)([O:3][C:4]([CH3:7])([CH3:6])[CH3:5])=[O:2]
Reactant: COc1ccc(B(O)O)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1
Reactant: CN(C(=O)OC(C)(C)C)c1cc(Br)ccn1
Product: COc1ccc(-c2ccnc(N(C)C(=O)OC(C)(C)C)c2)cc1CN(C(=O)c1sc2c(F)ccc(F)c2c1Cl)C1CCC(N(C)C(=O)OC(C)(C)C)CC1

Procedure:
Boronic acid 9 (520 mg, 0.83 mmol) is coupled to pyridyl bromide 160 (240 mg, 0.83 mmol) using Method A to give the title compound.
Reaction SMILES: C(OC([NH:8][C:9]([NH:26]C(OC(C)(C)C)=O)=[N:10][C:11]1[CH:16]=[C:15]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][N:18]=2)[CH:14]=[CH:13][C:12]=1[Cl:25])=O)(C)(C)C.[ClH:34]>ClCCl.O1CCOCC1>[ClH:25].[ClH:34].[Cl:25][C:12]1[CH:13]=[CH:14][C:15]([C:17]2[CH:22]=[C:21]([O:23][CH3:24])[CH:20]=[CH:19][N:18]=2)=[CH:16][C:11]=1[NH:10][C:9]([NH2:26])=[NH:8]
Reactant: COc1ccnc(-c2ccc(Cl)c(N=C(NC(=O)OC(C)(C)C)NC(=O)OC(C)(C)C)c2)c1
Agent: Cl
Solvent: C1COCCO1
Solvent: ClCCl
Product: COc1ccnc(-c2ccc(Cl)c(NC(=N)N)c2)c1
Temperature: 25 °C
Reaction time: 24 h

Procedure:
To a solution of N,N′-bis(tert-butoxycarbonyl)-N″-(2-chloro-5-(4-methoxypyridin-2-yl)phenyl)guanidine (133 mg) in dichloromethane (1 ml) was added a solution of hydrogen chloride in 1,4-dioxane (4N, 3 ml), and the mixture was stirred at room temperature for 24 hours. The solvent was evaporated under reduced pressure. To the residue was added 5% ethanol in ethyl acetate (100 ml), and the resultant precipitate was collected by filtration and dried under reduced pressure to give (2-chloro-5-(4-methoxypyridin-2-yl)phenyl)guanidine dihydrochloride (83 mg).
Reaction SMILES: Cl[C:2]1[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=1[N+:11]([O-])=O.C1(CN)CC1.[Cl:19][C:20]1[CH:57]=[CH:56][C:23]([C:24]2[C:29]([C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[C:35]([C:40]5[N:44](CC)[C:43]6C=C[C:49](C(O)=O)=[CH:50][C:42]=6N=5)[CH:36]=4)[N:31]=3)=[CH:28][C:27]([O:54][CH3:55])=[CH:26][CH:25]=2)=[CH:22][CH:21]=1>>[Cl:19][C:20]1[CH:57]=[CH:56][C:23]([C:24]2[C:29]([C:30]3[CH:39]=[CH:38][C:37]4[C:32](=[CH:33][CH:34]=[C:35]([C:40]5[N:44]([CH2:43][CH:42]6[CH2:50][CH2:49]6)[C:2]6[CH:10]=[CH:9][C:5]([C:6]([OH:8])=[O:7])=[CH:4][C:3]=6[N:11]=5)[CH:36]=4)[N:31]=3)=[CH:28][C:27]([O:54][CH3:55])=[CH:26][CH:25]=2)=[CH:22][CH:21]=1
Reactant: CCn1c(-c2ccc3nc(-c4cc(OC)ccc4-c4ccc(Cl)cc4)ccc3c2)nc2cc(C(=O)O)ccc21
Reactant: O=C(O)c1ccc(Cl)c([N+](=O)[O-])c1
Agent: NCC1CC1
Product: COc1ccc(-c2ccc(Cl)cc2)c(-c2ccc3cc(-c4nc5cc(C(=O)O)ccc5n4CC4CC4)ccc3n2)c1

Procedure:
The title compound was prepared from Resin 534a and cyclopropylmethylamine according to the procedure described in the preparation of Compound 534.
Reaction SMILES: [O:1]1[C:6]2[CH:7]=[CH:8][C:9]([N:11]3[CH2:15][CH:14]([CH2:16][CH2:17][NH:18][CH2:19][CH2:20][C:21]4[C:30]5[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[N:29]=5)[N:24]=[CH:23][CH:22]=4)[O:13][C:12]3=[O:33])=[CH:10][C:5]=2[O:4][CH2:3][CH2:2]1.CCN(C(C)C)C(C)C.Br[CH2:44][CH2:45][CH2:46][C:47]([O:49][CH2:50][CH3:51])=[O:48].[Na+].[I-]>C1COCC1>[CH2:50]([O:49][C:47](=[O:48])[CH2:46][CH2:45][CH2:44][N:18]([CH2:17][CH2:16][CH:14]1[O:13][C:12](=[O:33])[N:11]([C:9]2[CH:8]=[CH:7][C:6]3[O:1][CH2:2][CH2:3][O:4][C:5]=3[CH:10]=2)[CH2:15]1)[CH2:19][CH2:20][C:21]1[C:30]2[C:25](=[CH:26][CH:27]=[C:28]([O:31][CH3:32])[N:29]=2)[N:24]=[CH:23][CH:22]=1)[CH3:51]
Reactant: COc1ccc2nccc(CCNCCC3CN(c4ccc5c(c4)OCCO5)C(=O)O3)c2n1
Reactant: CCOC(=O)CCCBr
Agent: [I-]
Agent: [Na+]
Solvent: CCN(C(C)C)C(C)C
Solvent: C1CCOC1
Product: CCOC(=O)CCCN(CCc1ccnc2ccc(OC)nc12)CCC1CN(c2ccc3c(c2)OCCO3)C(=O)O1
Temperature: 80 °C
Yield: 68.4 %

Procedure:
A solution of the compound of Example 72 (0.2 g, 0.44 mmol) in THF (3 mL) was treated with DIPEA (0.147 mL, 2 eq.), ethyl 4-bromobutyrate (0.087 g, 1 eq.) and NaI (0.067 g, 1 eq.). The mixture was heated at 80° C. for 2 h, then partitioned between EA and water. The org. phase was dried over MgSO4 and concentrated. The residue was purified by FC (EA) to give the title compound as a yellowish oil (0.17 g, 68% yield).
Reaction SMILES: [CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11](=O)/[CH:12]=[CH:13]/N(C)C)[NH:8][CH:7]=1)=[O:5])[CH3:2].[CH3:18][O:19][C:20]1[CH:25]=[C:24]([N:26]2[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]2)[CH:23]=[CH:22][C:21]=1[NH:33][C:34]([NH2:36])=[NH:35].C(O)C>O>[CH2:1]([O:3][C:4]([C:6]1[CH:10]=[C:9]([C:11]2[CH:12]=[CH:13][N:36]=[C:34]([NH:33][C:21]3[CH:22]=[CH:23][C:24]([N:26]4[CH2:31][CH2:30][N:29]([CH3:32])[CH2:28][CH2:27]4)=[CH:25][C:20]=3[O:19][CH3:18])[N:35]=2)[NH:8][CH:7]=1)=[O:5])[CH3:2]
Reactant: COc1cc(N2CCN(C)CC2)ccc1NC(=N)N
Reactant: CCOC(=O)c1c[nH]c(C(=O)/C=C/N(C)C)c1
Solvent: O
Solvent: CCO
Product: CCOC(=O)c1c[nH]c(-c2ccnc(Nc3ccc(N4CCN(C)CC4)cc3OC)n2)c1
Temperature: 110 °C
Yield: 57.3 %

Procedure:
To a suspension of 5-((E)-3-Dimethylamino-acryloyl)-1H-pyrrole-3-carboxylic acid ethyl ester (1.7 g, 7.20 mmol) in 30 mL of ethanol N-[2-Methoxy-4-(4-methyl-piperazin-1-yl)-phenyl]-guanidine (1.9 g, 7.20 mmol) was added. The mixture was heated to 110° C. overnight. The resulting mixture was cooled at room temperature and diluted with water (70 mL). The solid was isolated by filtration, washed with 10 mL of water, dried in a vacuum oven at 40° C. affording to give 1.8 g (57% yield) of the title compound.
Reaction SMILES: [C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([C:25](=[O:33])[C:26]1[CH:31]=[CH:30][C:29]([CH3:32])=[CH:28][CH:27]=1)[CH:12]([C:15]1[NH:20][C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][N:17]2[N:16]=1)[CH2:13][CH3:14])([CH3:4])([CH3:3])[CH3:2].C(OC(=O)NCCCN(C(C1N(CC2C=CC(F)=CC=2)C(=O)C2=CC=CN2N=1)CC)C(=O)C1C=CC(C)=CC=1)(C)(C)C.[F:77][C:78]1[CH:79]=[C:80]([CH:83]=[CH:84][CH:85]=1)[CH2:81]Br>>[C:1]([O:5][C:6](=[O:34])[NH:7][CH2:8][CH2:9][CH2:10][N:11]([CH:12]([C:15]1[N:20]([CH2:81][C:80]2[CH:83]=[CH:84][CH:85]=[C:78]([F:77])[CH:79]=2)[C:19](=[O:21])[C:18]2=[CH:22][CH:23]=[CH:24][N:17]2[N:16]=1)[CH2:13][CH3:14])[C:25](=[O:33])[C:26]1[CH:27]=[CH:28][C:29]([CH3:32])=[CH:30][CH:31]=1)([CH3:2])([CH3:4])[CH3:3]
Reactant: Fc1cccc(CBr)c1
Reactant: CCC(c1nn2cccc2c(=O)[nH]1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Agent: CCC(c1nn2cccc2c(=O)n1Cc1ccc(F)cc1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Product: CCC(c1nn2cccc2c(=O)n1Cc1cccc(F)c1)N(CCCNC(=O)OC(C)(C)C)C(=O)c1ccc(C)cc1
Yield: 13.5 %

Procedure:
(±)-(3-{(4-Methylbenzoyl)-[1-(4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4] triazin-2-yl)-propyl]amino}propyl)carbamic acid tert-butyl ester (Example 3 A, 42 mg, 0.09 mmol) was converted to the title compound (7 mg, 13%) in a manner similar to the preparation of (±)-{3-[{1-[3-(4-fluorobenzyl)-4-oxo-3,4-dihydropyrrolo[2,1-f][1,2,4]triazin-2-yl]-propyl}-(4-methylbenzoyl)-amino]-propyl}-carbamic acid tert-butyl ester, except that 3-fluorobenzyl bromide (22 mg, 0.12 mmol) was used instead of 4-fluorobenzyl bromide: 1H NMR (CDCl3) δ 7.45–6.96 (m, 10H), 6.62 (m, 1H), 5.95 (m, 1H), 5.86 (m, 1H), 4.90 (m, 1H), 3.86 (m, 1H), 3.33 (m, 2H), 2.71 (m, 2H), 2.39 (s, 3H), 2.05 (m, 1H), 1.85 (m, 1H), 1.60 (m, 1H), 1.40 (s, 9H), 1.05 (m, 1H), 0.72 (m, 3H).
Reaction SMILES: [N:1]1[C:10]2[C:5](=[CH:6][CH:7]=[CH:8][N:9]=2)[C:4](O)=[CH:3][CH:2]=1.[Br-:12].[Br-].[Br-].[P+3]=O.N>C(#N)C>[Br:12][C:4]1[C:5]2[C:10](=[N:9][CH:8]=[CH:7][CH:6]=2)[N:1]=[CH:2][CH:3]=1
Reactant: [Br-]
Reactant: Oc1ccnc2ncccc12
Agent: N
Agent: O=[P+3]
Solvent: CC#N
Product: Brc1ccnc2ncccc12
Reaction time: 1 h

Procedure:
To a solution of 1,8-naphthyridin-4-ol (59 g, 400 mmol) in acetonitrile (500 ml) was added phosphorus oxide tribromide. The reaction mixture was heated to reflux. After 1 hour, the reaction mixture was carefully diluted with ice and the resulting solution was basified with ammonia solution (25%) to pH>7. The reaction mixture was partially concentrated in vacuo, then extracted with chloroform (4×500 ml). The organics were dried over sodium sulfate, filtered, and concentrated in vacuo. The residue was purified by column chromatography on silica gel (ethyl acetate/petroleum ether gradient) to afford 4-bromo-1,8-naphthyridine.